Phenyl ester side chains to increase polymer resorptivity

ABSTRACT

The present invention relates to polymers modified to increase their resorbability. In particular, the polymers of the invention have phenyl ester side chains which are good leaving groups and which thereby increase the resorption rate of the polymer relative to the same polymer, for example, bearing a comparable amount of an alkyl ester side chain. Such polymers are generally water insoluble, but when modified are able to solublize drugs and upon degradation and resorption, release those in a physiological environment in a controlled and/or sustained manner.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of PCT Application NumberPCT/US2008/067715 filed Jun. 20, 2008 which claims priority to U.S.Provisional Application Ser. No. 60/945,508 filed Jun. 21, 2007 thedisclosures of which are each herein incorporated by reference in theirentirety for all purposes.

BACKGROUND OF THE INVENTION

Biocompatible, biodegradable polymers have diverse medical uses andoften provide controlled or sustained drug delivery—whether frompharmaceutical compositions, as medical devices, or when used inconjunction with medical devices. Pharmaceutical compositions can bedesigned for many, if not all known medicinal delivery routes, includingoral, intramuscular, subcutaneous, intraarticular, intranasal, topical,or other delivery route using biocompatible polymers. Such polymers arealso used for controlled drug delivery in conjunction with medicaldevices and prostheses. For example, biocompatible polymers and drugshave been applied as coatings to implantable medical devices to providecontrolled or sustained drug release. Applying a polymer coatingprovides one strategy to change the physicomechanical properties of theunderlying device and can improve handling during surgical procedures.Additionally, medical devices, e.g., surgical meshes, bone prosthesesand surgical closure devices, can be formed from or include a componentwith biocompatible polymers. Such devices can also have drugsincorporated at the time of manufacture and or later by post-manufacturecoating or impregnation.

The profile of drug release depends on many factors, including polymerproperties, drug properties, delivery route, delivery mode, othercomponents that may be present or relevant such as individualmetabolism, enzymatic action, degree of vascularization and more.Moreover, there are often manufacturing and compatibility challengessuch as drug solubility or temperature sensitivity, that arise whenselecting a polymer-drug system or formulation that provides a desiredrelease profile yet remains biocompatible without untoward side effectsin a subject. Given the diversity of polymers, drugs and medicalapplications, there is always a need for new polymers to providepolymer-drug combinations that can be manipulated to suit the medicalcondition or need. The present invention addresses the need forbiocompatible, biodegradable and resorbable polymers that can be used tocreate medicines or to use with, in, on or as part of medical devices toprovide the clinician with greater options for drug delivery, includingfor controlled, sustained or defined periods of drug release.

Finally, use of the polymers of the present invention provide a novelmethod to generate free carboxylic acid groups during in vivo use(rather than at the time of polymer synthesis and have certain syntheticadvantages), and thus provide polymers with a greater range of chemicalproperties as well as the greater drug delivery capabilities.

SUMMARY OF THE INVENTION

The present invention is directed to resorbable polymers that arebiocompatible, biodegradable polymers capable of resorption underphysiological conditions. In one embodiment, the polymers of theinvention comprise one or more monomer units represented by Formula I:

wherein “Monomer” represents the repeating unit of a biocompatible,biodegradable polymer capable of resorption under physiologicalconditions and has a phenyl ester side chain such that R′ is phenyl-R.

In particular, “Monomer” represents the repeating unit of abiocompatible, biodegradable polymer capable of resorption underphysiological conditions;

R′ is phenyl-R, wherein from zero to five R substituents are present atany position on the phenyl ring, and each R is independently linear orbranched, substituted or unsubstituted, saturated or unsaturated alkyl,aryl, alkylaryl, heteroatom-containing alkyl or aryl, alkylcycloalkyl,alkoxy, aryloxy or alkylether having from 1 to 20 carbon atoms; halide;nitro; —(R₂)_(r)O((CR₃R₄)_(a)O)_(s)—R₅; —O((CR₃R₄)_(a)O)_(s)—R₅;—C(O)—R₅; —(R₂)_(b)C(O)—YR₆; a protected hydroxyl group; a protectedamino group or a protected carboxylic acid group;

Y is —O— or —NH—;

each R₂ is independently linear or branched, lower alkylene or loweralkenylene;

each R₃ and R₄ is independently hydrogen, or linear or branched loweralkyl;

each R₅ is independently linear or branched, substituted orunsubstituted, saturated or unsaturated alkyl;

each R₆ is hydrogen; saturated or unsaturated alkyl, aryl or alkylarylhaving from 1 to 20 carbon atoms; or —(R₂)_(r)O((CR₃R₄)_(a)(O)_(s)—R₅;

each a is independently 1 to 4;

each b is independently zero or one;

each r is independently 1 to 4; and

each s is independently 1 to 5000.

In particular embodiments, the polymers of the invention comprise fromat least about 0.1% to 100% of Monomer and thus include copolymers andhomopolymers.

In another embodiment, the polymers of the invention comprise one ormore diphenol monomer units represented by Formula II:

These diphenol monomer units provide biocompatible, biodegradablepolymers with pendant phenyl ester side chains, which polymers arecapable of resorption under physiological conditions

In particular,

A is —C(O)—, —C(O)—R₁—C(O)—, —C(═NH)—, —C(O)—NH—R₁—NH—C(O)— or —C(S)—;

B is a trivalent, linear or branched, substituted or unsubstitutedalkyl, alkenyl, aryl or alkylaryl moiety having 1-20 carbon atoms, or is

each backbone aromatic ring has from zero to four Z₁ or Z₂ substituents,each of which is independently selected from the group consisting ofhalide, lower alkyl, alkoxy, nitro, alkylether, a protected hydroxylgroup, a protected amino group and a protected carboxylic acid group;

the pendant phenyl ring has from zero to five R substituents at anyposition on the phenyl ring, and each R is independently linear orbranched, substituted or unsubstituted, saturated or unsaturated alkyl,aryl, alkylaryl, heteroatom-containing alkyl or aryl, alkylcycloalkyl,alkoxy, aryloxy or alkylether having from 1 to 20 carbon atoms; halide;nitro; —(R₂)_(r)O((CR₃R₄)_(a)O)_(s)—R₅; —O((CR₃R₄)_(a)O)_(s)—R₅;—C(O)—R₅; —(R₂)_(b)C(O)—YR₆; a protected hydroxyl group; a protectedamino group or a protected carboxylic acid group;

R₁ is, independently, a divalent, linear or branched, substituted orunsubstituted alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkylene oxideor arylene oxide moiety having from 1 to 30 carbon atoms;—(R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r); or—(R₂)_(r)CO₂((CR₃R₄)_(a)O)_(s)CO(R₂)_(r);

each R₂ is independently linear or branched, lower alkylene or loweralkenylene;

each R₃ and R₄ is independently hydrogen, or linear or branched loweralkyl;

R₅ is independently linear or branched, substituted or unsubstituted,saturated or unsaturated alkyl;

R₆ is hydrogen; saturated or unsaturated alkyl, aryl or alkylaryl havingfrom 1 to 20 carbon atoms; or —(R₂)_(r)O((CR₃R₄)_(a)O)_(S)—R₅;

R₇ is independently a bond, or linear or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl having from 1 to 20 carbonatoms, and when substituted, the substituent can be, but is not limitedto, —X, —CX₃, —CHX₂, —CH₂X, —NHR₉, or —NHC(O)R₁₀;

R₈ is independently a bond or linear or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl having from 1 to 20 carbonatoms, and when substituted, the substituent can be, but is not limitedto, —X, —CX₃, —CHX₂, —CH₂X, —NHR₉, or —NHC(O)R₁₀;

R₉ is a linear or branched, substituted or unsubstituted, saturated orunsaturated alkyl, aryl or alkylaryl group or an amino protecting group;

R₁₀ is a linear or branched alkyl, aryl or alkylaryl group;

X is a halogen;

Y is —O— or —NH—;

each a is independently 1 to 4;

each b is independently zero or one;

each r is independently 1 to 4; and

each s is independently 1 to 5000.

In some embodiments, the polymers of the invention comprise from atleast about 0.1% to 100% of these diphenol monomer units.

In other embodiments, the polymers have A as —C(O)—R₁—C(O) and B as

wherein R₁ is methylene, ethylene or n-propylene, and R₇ and R₈ arepreferably a bond, methylene or ethylene.

When the polymers of the invention are copolymers containing a Monomeror a diphenol monomer unit of Formula II, then the other monomer unitsof those copolymers can be nearly the same as the Monomer or thediphenol monomer unit of Foimula II, except that the phenyl ester moietycan be replaced by hydrogen (to form a free COOH group), by anotherester class such as alkyl esters, alkylaryl esters, or esters withalkylene oxide chains or ether chains, by amides or by anothercompatible functional group. Further, in addition to the foregoingchanges or instead of the foregoing changes, the other monomer units canbe similar to the Monomer or the diphenol monomer units of Formula IIbut have variability among the different substituents, i.e., differencescan reside at any of A, B, R₁-R₁₀, X, Y or the other variables ofFormulas I and II. Finally, the other monomer units in the copolymer canbe substantially different provided such moieties preserve theproperties of the polymer and are capable of copolymerizing with theMonomer or the diphenol monomeric unit of Formula II.

A further aspect of the invention is directed to polymers of theinvention blended with one or more second polymers. The second polymersare also biocompatible but can be biodegradable, resorbable or stable asneeded for the particular use, whether formed into a device, on a device(as by coating, a film or the like), as a pharmaceutical composition tomanipulate drug elution profile and the like. Particularly useful secondpolymers, especially for fully resorbable products, include polyethyleneglycol (PEG), poly(D,L-lactide) (PLA), polyglycolic acid [polyglycolide(PGA)], poly(D,L-lactide-co-glycolide) (PLGA) and other diphenol-derivedor tyrosine-derived polyarylates. The polymers blends of the inventioncan further include one or more drugs.

In another aspect of the invention, the polymers and blends of theinvention are formulated into pharmaceutical compositions comprising oneor more drugs, and optionally, one or more pharmaceutically-acceptablecarriers. Such drugs include, but are not limited to, antimicrobialagents, anesthetics, anti-inflammatory agents, anti-scarring agents,growth factors and anti-fibrotic agents.

In a further aspect, the invention is directed to a medical devicecomprising one or more of the polymers or blends of the invention, withor without one or more drugs. Moreover, the medical device can be coatedwith one or more of the polymers or blends of the invention. Suchdevices include but are not limited to, implantable or insertabledevices such as stents; surgical meshes; coverings, pouches, pockets,bags and the likes for devices; wound closure adjuncts and any type ofcatheter. Coatings, when present, can be on any surface of the device,as a partial or full coating, and can be single or multi-layered, usingthe present polymers and blends or using layers made from otherbiocompatible polymers.

Yet another aspect of the invention provides monomeric compoundsrepresented by Formula III or IV

These monomeric compounds have phenyl esters moieties and can be used inthe synthesis of the polymers of the invention, namely thebiocompatible, biodegradable polymers capable of resorption underphysiological conditions. Compounds of Formula III have free hydroxylsand those of Formula IV have hydroxyl protecting groups (P). The othersubstituents are as described above for the diphenol monomeric units ofFormula II. In a preferred embodiment, the monomeric compounds of theinvention are those wherein B is

In a still further aspect, the instant invention provides methods oftreating a disorder or condition in a patient by implanting a medicaldevice of the invention in a patient, with or without one or moredrug(s). Implantable medical devices of the invention can be used totreat or ameliorate a cardiovascular disorder, a neurological disorder,a hernia or hernia-related disorder, an ophthalmic condition, or toeffectuate an anatomical repair, reconstruction, replacement oraugmentation of a body part, limb, tissue or organ of a patient. Forexample, these methods can ameliorate the morbidities associated withimplantation of a comparable untreated medical device.

Such morbidities include scarring, pain and infection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 graphically illustrates the change in polymer molecular weight invivo as a function of time for (♦) poly(DTM-15-DT glutarate), (⋄)poly(DTPB glutarate), (●) poly(DTMB succinate), (□) poly(DTMBglutarate), (▴) poly(DT(DATE) glutarate) and (∘) poly(DTMB-10-DTsuccinate).

FIG. 2 graphically illustrates the mass loss from polymer coated meshesin vivo as a function of time for (♦) poly(DTM-15-DT glutarate), (⋄)poly(DTPB glutarate), (●) poly(DTMB succinate), (□) poly(DTMBglutarate), (▴) poly(DT(DATE)glutarate) and (∘) poly(DTMB-10-DTsuccinate).

FIG. 3 shows the release profiles of rifampin from poly(DTMB glutarate)a spray-coated polypropylene mesh.

DETAILED DESCRIPTION OF THE INVENTION

In most embodiments, the present invention relates tomedically-relevant, biodegradable polymers with carboxylic acid sidechains protected by facile leaving groups. In particular, these leavinggroups are phenyl esters, which upon cleavage in situ, generate freecarboxylic acid groups on the polymer to thereby increase polymerdegradation and resorbability. The present invention is also directed topharmaceutical compositions comprising the polymers of the invention andone or more drugs as well as medical devices made from or coated with apolymer of the invention, and optionally, with one or more drugs.

DEFINITIONS AND ABBREVIATIONS

The compounds herein described may have asymmetric centers. All chiral,diastereomeric, and racemic forms are included in the present invention.Geometric isomers of olefins and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention.

By “stable compound” or “stable structure” is meant herein a compound ormolecule that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and for formulation into oruse into an efficacious therapeutic agent.

As used herein, unless otherwise clear from the context, “alkyl” meansboth branched- and straight-chain, saturated aliphatic hydrocarbongroups having the specified number of carbon atoms. Straight and linearare used interchangeably. As used herein “lower alkyl” means an alkylgroup having 1 to 6 carbon atoms. When substituted, the substituents caninclude halide, alkyl, alkoxy, hydroxy, amino, cyan, nitro,trifluoromethyl, trifluoroethyl, additional substituents as describedherein, and the like compatible with the properties and synthesis of themolecules of the invention.

As used herein, “alkenyl” means hydrocarbon chains of either a straightor branched configuration having one or more unsaturated carbon-carbondouble bonds, such as ethenyl, propenyl, and the like. “Lower alkenyl”is an alkenyl group having 2 to 6 carbon atoms. As used herein,“alkynyl” means hydrocarbon chains of either a straight or branchedconfiguration having one or more carbon-carbon triple bonds, such asethynyl, propynyl and the like. “Lower alkynyl” is an alkynyl grouphaving 2 to 6 carbon atoms. When the number of carbon atoms is notspecified, then alkyl, alkenyl and alkynyl means having from 1-20 carbonatoms. Alkylene and alkenylene groups are alkyl groups and alkenylgroups, respectively, which are divalent. When substituted, thesubstituents can include halide, alkyl, alkoxy, hydroxy, amino, cyano,nitro, trifluoromethyl, trifluoroethyl, additional substituents asdescribed herein, and the like compatible with the properties andsynthesis of the molecules of the invention.

As used herein, “saturated or unsaturated alkyl” refers to any of analkyl group an alkenyl group or an alkynyl group, having any degree ofsaturation, i.e., completely saturated (as in alkyl), one or more doublebonds (as in alkenyl) or one or more triple bonds (as in alkynyl).

Examples of alkyl groups include but are not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl,n-heptyl, n-octyl, isooctyl, nonyl, decyl, and the like; alkylene andalkenylene groups include but are not limited to, methylene, ethylene,propylenes, propenylene, butylenes, butadiene, pentene, n-hexene,isohexene, n-heptene, n-octene, isooctene, nonene, decene, and the like.Those of ordinary skill in the art are familiar with numerous linear andbranched hydrocarbon groups. Alkynyl groups include ethynyl and propynylgroups.

As used herein, “aryl” means any stable 6- to 14-membered monocyclic,bicyclic or tricyclic ring, containing at least one aromatic carbonring, for example, phenyl, naphthyl, indanyl, tetrahydronaphthyl(tetralinyl) and the like. When substituted, the substituents caninclude halide, alkyl, alkoxy, hydroxy, amino, cyano, nitro,trifluoromethyl, trifluoroethyl, additional substituents as describedherein, and the like compatible with the properties and synthesis of themolecules of the invention.

As used herein, the term “heteroaryl” means a stable 5- to 10-memberedmonocyclic or bicyclic heterocyclic ring which is aromatic, and whichconsists of carbon atoms and from 1 to 3 heteroatoms selected from thegroup consisting of N, O and S and wherein the nitrogen can optionallybe quaternized, and including any bicyclic group in which any of theabove-defined heteroaryl rings is fused to a benzene ring. Theheteroaryl ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The presence ofsubstitution on the heteroaryl group is optional and can be on a carbonatom, a nitrogen atom or other heteroatom if the resulting compound isstable and all the valencies of the atoms have been satisfied. Whenpresent, the substituents of the substituted heteroaryl groups are thesame as for the substituted aryl groups and also include alkylammoniumsalts when the substituent is an alkyl group attached to the nitrogenatom of the heteroaryl ring. These quarternized ammonium salts includehalides, hydrohalides, sulfates, methosulfates, methanesulfates,toluenesulfates, nitrates, phosphates, maleates, acetates, lactates orany other pharmaceutically acceptable salt. Examples of heteroarylgroups include, but are not limited to, pyridyl, pyrimidinyl, furanyl,thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,benzothienyl, indolyl, indolenyl, quinolinyl, isoquinolinyl andbenzimidazolyl.

As used herein, “alkylaryl” refers to an aryl group attached to an alkylgroup, which in turn is the attachment point of the substituent. Thearyl group of this moiety can optionally be substituted in accordancewith the definitions herein. For example, a benzyl ester represents analkylaryl moiety in which the methylene attached on the phenyl ring isbonded to the oxygen of the ester. In contrast, for phenyl esters, thephenyl ring is directly bonded to the oxygen of the ester.

The term “substituted” as used herein means that one or more hydrogenson the designated atom are replaced with a selection from the indicatedgroups, provided that the designated atom's normal valency is notexceeded, and that the substitution results in a stable compound. If nosubstituent is indicated then the valency is filled with a hydrogenatom. The substituents of the invention can include, as indicated,halide (also referred to as halo), hydroxy, alkyl, alkoxy, amino, cyano,nitro, trifluoromethyl, aryl, heteroaryl, monoalkylamino, dialkylamino,trialkylammonium and salts thereof, carbamoyl, acylamino,arylcarbonylamino, alkoxycarbonylamino, formamido, guanidino, ureido,sulfamyl, and alkylsulfonamido. These groups can be substituents foralkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl andheteroaralkyl groups as indicated In accordance with various embodimentsof the invention and provided the presence of the substituent iscompatible with the properties and synthesis of the molecules of theinvention.

The terms “radical,” “group,” “functional group,” and “substituent” canbe used interchangeably in some contexts and can be used together tofurther describe a chemical structure. For example, the term “functionalgroup” can refer to a chemical “group” or “radical,” which is a chemicalstructure variable that can be in-chain, pendant and/or terminal to thechemical structure. A functional group may be substituted.

A “halide” or a “halo” group is a halogen atom, and includes fluoro,chloro, bromo and iodo groups. The term “alkoxy” refers to an alkylgroup having at least one oxygen substituent represented by R—O—.

Examples of poly(alkylene glycols) include, but are not limited to,poly(ethylene oxide)(PEG), poly(propylene glycol)(PPG),poly(tetramethylene glycol), and any derivatives, analogs, homologues,congeners, salts, copolymers and combinations thereof. In someembodiments, the poly(alkylene glycol) is PEG.

As used herein, “therapeutically-effective amount” refers to that amountof a drug or bioactive agent necessary to administer to a host toachieve a desired therapeutic effect in treating, ameliorating orpreventing a disease or condition. For example, atherapeutically-effective amount can be that amount to provideantimicrobial activity, pain relief, anti-inflammatory activity,antifibrotic activity, anti-tumor or cancer activity and the likeassociated with the particular drug or biological agent in use.Therepeutically-effective amounts for known drugs are available in theliterature or can be determined, for new or known drugs, using art knownmethods, techniques and standards.

As used herein, “phainiaceutically acceptable salts” refer toderivatives of the disclosed compounds that are modified by making acidor base salts. Examples include, but are not limited to, mineral ororganic acid salts of basic residues such as amines; alkali or organicsalts of acidic residues such as carboxylic acids, and the like.Pharmaceutically acceptable salts include, but are not limited to,hydrohalides, sulfates, methosulfates, methanesulfates,toluenesulfonates, nitrates, phosphates, maleates, acetates, lactatesand the like. Pharmaceutically-acceptable salts of the compounds of theinvention can be prepared by methods know to those of skill in the art.

Abbreviations used herein for naming polymers and the subunits thereofinclude B, 4-hydroxybenzoic acid; Bn or Bz, benzyl; D or DAT,desaminotyrosine or desaminotyrosyl; DATE, desaminotyrosine ethyl ester;dig, diglycolate; E or Et, ethyl; glu, glutarate; M or Me, methyl; MB,methylparaben; PB, propyl paraben; PEG, polyethylene glycol; succ,succinate; and T, tyrosine.

The nomenclature for the polymers based on diphenol monomer units havetwo part names. The first part identifies the diphenol moiety and thesecond part (the A group) identifies the group with which the diphenolmoiety is copolymerized. The names are written in the form poly(diphenoldiacid), poly(diphenol carbonate), poly(diphenol iminocarbonate), etc.

The diphenol moiety is generally named for its three components, the twoaromatic ring moieties and the tyrosine ester moiety. For example, DTEis desaminotyrosyl-tyrosine ethyl ester; DTBn isdesaminotyrosyl-tyrosine benzyl ester. When a free acid is present(rather than an ester), the name for a third component is omitted. Thus,DT is the corresponding free acid form, namely desaminotyrosyl-tyrosine.Also for example, DT(DATE) is the desaminotyrosine ethyl ester (DATE) asthe ester on the tyrosine of DT. For a paraben, the diphenol monomerdesaminotyrosyl-tyrosine methyl paraben is abbreviated as DTMB; thecorresponding propylparaben is DTPB.

The second part of the name identifies the group with which the diphenolmoiety is polymerized, such as the diacid, the carbonate, theiminocarbonate and the like. Hence, specific examples include poly(DTEglutarate), poly(DTPB succinate), poly(DTBn carbonate) and the like.

If a mixture of diphenol moieties or of copolymerized groups (such astwo diacids) are present in the polymer, then that part of name mayincludes the designation “co” or may have a hyphen, along with anindication of percentage of one of the two moieties. For example,poly(DTE-co-10-DT succinate) and poly(DTE-10-DT succinate) are usedinterchangeably to mean a polymer made by copolymerizing a mixture of90% desaminotyrosyl-tyrosine ethyl ester and 10%desaminotyrosyl-tyrosine with the diacid succinate. An example of amixed diacid is poly(DTMB PEG-bis-succinate-50-adipate).

Polymer Description

The present invention relates to biocompatible, biodegradable polymerscomprising monomer units with pendant phenyl ester (PE) groups, i.e., PEside chains relative to the polymer backbone. When those PE groups arecleaved, removed, degraded or otherwise released from the polymer invitro, in vivo, in situ (i.e., under physiological conditions), theresult is an increase in the free acid content of the polymer, asignificant increase in hydrophilicity and an increase in the rate ofdegradation of the polymer backbone. Without wishing to be bound by amechanism, when the polymer is driven to breakdown more quickly intomore water-soluble constituents, the result is faster resorption. Hence,the present invention is directed to resorbable polymers having pendantphenyl esters.

A biocompatible polymer is a polymer which is compatible with livingtissue or a living system and is acceptable for use in or by animals orhumans. Thus, a biocompatible polymer does not cause physiological harmto any significant or unacceptable degree, does not cause any or anysignificant amount of inflammation or immunological reaction, and is nottoxic or injurious to the living tissue or system. For example, abiocompatible polymer can be ingested, implanted, placed on or otherwiseused in a living subject or tissue without untoward effects.

As used herein, a “biodegradable polymer” is a biocompatible polymerthat is hydrolytically labile, oxidatively labile, or susceptible toenzymatic action, or any combination thereof, which action leads to thebreakdown, whether partial or complete, of the polymer. It should beunderstood that polymers which are biodegradable have variableresorption times, which can depend, for example, on the nature and sizeof the breakdown products.

As used herein a “resorbable polymer,” is a biocompatible,biodegradable, polymer (1) with repeating backbone units that arechemically unstable under physiological conditions, i.e., in thepresence of water, enzymes or other cellular processes, that is, thepolymer is biodegradable, (2) whose degradation products are capable ofbeing taken up and/or assimilated in vivo or under physiologicalconditions by any mechanism (including by absorption, solubilization,capillary action, osmosis, chemical action, enzymatic action, cellularaction, dissolution, erosion and the like or any combination of theseprocesses) in a subject on a physiologically-relevant time scaleconsonant with the intended use of the polymer, and (3) when modified tohave pendant PE groups, those PE groups are facile leaving groups whichwhen removed increase the free acid content of the polymer and therebyincrease its hydrophilicity, increase the rate of degradation of thepolymer backbone and increase the resorption time of the polymerrelative to the same polymer having a comparable amount of pendant PEgroups present as pendant aliphatic esters.

Resorbable polymers contain cleavable backbone bonds, that when broken,produce smaller water soluble fragments, which themselves may bepolymeric or monomeric. These smaller fragments are or can be (asneeded) further degraded to a size that can be engulfed by a macrophage,processed by a cell or otherwise removed from the cellular milieu ortissues at the physiological site of use, resulting in complete orsubstantially complete resorption of the polymer in a specified time.

When resorbable polymers become completely or substantially resorbed,then the polymer (but not necessarily the monomeric repeating unitsthereof or smaller polymeric fragments thereof) is no longer present ordetectable in the subject. For example, if the polymer is a coating onan implanted medical device, the polymer would no longer be present onor detectable on the device after resorption. Similarly, if the polymeris formed into a medical device (e.g., suture material, a staple, adevice covering, an implant, a plug, a drug or vaccine carrier), thenthe device is no longer present or detectable at the physiological siteof use. Without wishing to be bound, one can describe this process asconversion of a water-insoluble polymer into water soluble components orsubunits by break down into its components with concomitant eliminationor excretion.

The time scale of resorption depends upon the intended use and thepolymers of the invention can be manipulated to provide for rapidresorption, e.g., within a few days, to longer periods, such as weeks ormonths, under physiological conditions. Medically-relevant time periodsinclude, e.g., from 1-30 days and from 1 to 24 months, as well as alltime in between such as 5 days, 1-6 weeks, 2, 3, 4, 6 or months and thelike.

Accordingly, resorbable polymers of the invention include, but are notlimited to, polyesters, polycarbonates, polyarylates, polyamides,polyesteramides, polyurethanes, polyethers, polyphosphoesters,polyiminocarbonates, polyureas, polyphosphates, polyhydrazides,polyanhydrides, and polyphosphazenes which have pendant phenyl estergroups.

Examples of biocompatible polymers that degrade hydrolytically, include,but are not limited to, polyesters, polycarbonates, polyarylates,polyesteramides, polyurethanes, polyethers, polyphosphoesters,polyiminocarbonates, polyphosphates, and polyanhydrides. Examples ofbiocompatible polymers that can be degraded enzymatically include, butare not limited to, polyesters, polyamides, polyesteramides andpolyphosphates.

Accordingly, certain embodiments of the invention are directed topolymers comprising monomers represented by the formula (I):

wherein

“Monomer” represents the repeating unit of a biocompatible,biodegradable polymer capable of resorption under physiologicalconditions;

R′ is phenyl-R, wherein from zero to five R substituents are present atany position on the phenyl ring, and each R is independently linear orbranched, substituted or unsubstituted, saturated or unsaturated alkyl,aryl, alkylaryl, heteroatom-containing alkyl or aryl, alkylcycloalkyl,alkoxy, aryloxy or alkylether having from 1 to 20 carbon atoms; halide;nitro; —(R₂)_(r)O((CR₃R₄)_(a)O)_(s)—R₅; —O((CR₃R₄)_(a)O)_(s)—R₅;—C(O)—R₅; —(R₂)_(b)C(O)—YR₆; a protected hydroxyl group; a protectedamino group or a protected carboxylic acid group;

Y is —O— or —NH—;

each R₂ is independently linear or branched, lower alkylene or loweralkenylene;

each R₃ and R₄ is independently hydrogen, or linear or branched loweralkyl;

each R₅ is independently linear or branched, substituted orunsubstituted, saturated or unsaturated alkyl;

each R₆ is hydrogen; saturated or unsaturated alkyl, aryl or alkylarylhaving from 1 to 20 carbon atoms; or —(R₂)_(r)O((CR₃R₄)_(a)O)_(s)—R₅;

each a is independently 1 to 4;

each b is independently zero or one;

each r is independently 1 to 4; and

each s is independently 1 to 5000.

The substituents of the Monomer unit of the polymers comprise thebackbones, for example, of polyesters, polycarbonates, polyarylates,polyamides, polyesteramides, polyurethanes, polyethers,polyphosphoesters, polyiminocarbonates, polyureas, polyphosphates,polyhydrazides, polyanhydrides, polyphosphazenes and the like.

In general, these polymers contain from at least about 0.1% to 100% ofmonomer units with the above-defined phenyl ester group.

In another embodiment, the invention is directed to polymers comprisingone or more diphenol monomer units represented by the Formula (II)

wherein

A is —C(O)—, —C(O)—R₁—C(O)—, —C(═NH)—, —C(O)—NH—R₁—NH—C(O)— or —C(S)—;

B is a trivalent, linear or branched, substituted or unsubstitutedalkyl, alkenyl, aryl or alkylaryl moiety having 1-20 carbon atoms, or is

each backbone aromatic ring has from zero to four Z₁ or Z₂ substituents,each of which is independently selected from the group consisting ofhalide, lower alkyl, alkoxy, nitro, alkylether, a protected hydroxylgroup, a protected amino group and a protected carboxylic acid group;

the pendant phenyl ring has from zero to five R substituents at anyposition on the phenyl ring, and each R is independently linear orbranched, substituted or unsubstituted, saturated or unsaturated alkyl,aryl, alkylaryl, heteroatom-containing alkyl or aryl, alkylcycloalkyl,alkoxy, aryloxy or alkylether having from 1 to 20 carbon atoms; halide;nitro; —(R₂)_(r)O((CR₃R₄)_(a)O)_(s)—R₅; —C(O)—R₅; —(R₂)_(b)C(O)—YR₆; aprotected hydroxyl group; a protected amino group or a protectedcarboxylic acid group;

R₁ is, independently, a divalent, linear or branched, substituted orunsubstituted alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkylene oxideor arylene oxide moiety having from 1 to 30 carbon atoms;—(R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r); or—(R₂)_(r)CO₂((CR₃R₄)_(a)O)_(s)CO(R₂)_(r);

each R₂ is independently linear or branched, lower alkylene or loweralkenylene;

each R₃ and R₄ is independently hydrogen, or linear or branched loweralkyl;

R₅ is independently linear or branched, substituted or unsubstituted,saturated or unsaturated alkyl;

R₆ is hydrogen; saturated or unsaturated alkyl, aryl or alkylaryl havingfrom 1 to 20 carbon atoms; or —(R₂)_(r)O((CR₃R₄)_(a)O)_(S)—R₅;

R₇ is independently a bond, or linear or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl having from 1 to 20 carbonatoms, and when substituted, the substituent can be, but is not limitedto, —X, —CX₃, —CHX₂, —CH₂X, —NHR₉, or —NHC(O)R₁₀;

R₈ is independently a bond or linear or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl having from 1 to 20 carbonatoms, and when substituted, the substituent can be, but is not limitedto, —X, —CX₃, —CHX₂, —CH₂X, —NHR₉, or —NHC(O)R₁₀;

R₉ is a linear or branched, substituted or unsubstituted, saturated orunsaturated alkyl, aryl or alkylaryl group or an amino protecting group;

R₁₀ is a linear or branched alkyl, aryl or alkylaryl group;

X is a halogen;

Y is O or NH;

each a is independently 1 to 4;

each b is independently zero or one;

each r is independently 1 to 4; and

each s is independently 1 to 5000.

These polymers of the invention can be homopolymers or copolymers. Whenthe polymers are copolymers, they contain from at least about 0.1% to100% of the diphenol monomer units, from at least about 1%, 2%, 3%, 4%,5%, 6%, 8%, 10%, 12% to about 30%, 40%, 50%, 60%, 75%, 90%, 95% or 99%in any combination of ranges. In certain embodiments, the range ofdiphenol monomer units with phenyl esters (i.e., those represented byFormula II) in the polymer is from about 5 to about 50%. Additionally,the polymer can have combinations of two or more different diphenolmonomer units with pendant phenyl ester groups, where the difference canbe in the diphenol moiety, the phenyl ester moiety or the A moiety ofthe molecule. Additionally, the copolymers can have varying ratios ofthe A moiety when applicable, e.g., two different diacids or twodifferent urethanes.

Examples of polymers of the invention having A as a diacid and mixed R₁groups such that R₁ ranges overall from about 10% to about 50%bis-carboxypolyethylene glycol with the remaining R₁ being alkylene orR₁ ranges overall from about 10% to about 50% PEG-bis-succinate orPEG-bis-glutarate with the remaining R₁ being alkylene. Preferredalkylene groups for these polymers form the diacids succinic acid,glutaric acid, adipic acid or suberic acid.

When the polymer is a copolymer of one or more diphenol monomer unitswith a phenyl ester In accordance with various embodiments of theinvention and other monomer units, then those other monomer units areany other compatible monomer unit that can polymerize with a diol andthe A moiety of the diphenol moiety.

Hence those polymers of the invention which are copolymers containing aMonomer or a diphenol monomer unit of Formula II, can have other monomerunits that are nearly the same as the Monomer or the diphenol monomerunit of Formula II, except that the phenyl ester moiety can be replacedby hydrogen (to form a free COOH group), by another ester class such asalkyl esters, alkylaryl esters, or esters with alkylene oxide chains orether chains, by amides or by another compatible functional group.Alternatively, these slight variations can be combined with others wherethe other monomer units are similar to the Monomer or the diphenolmonomer units of Formula II but now the have variability resides amongthe different substituents, i.e., the changes are in any of A, B,R₁-R₁₀, X, Y or the other variables of Formulas I and II. Finally, theother monomer units in the copolymer can be substantially differentprovided such moieties preserve the properties of the polymer and arecapable of copolymerizing with the Monomer or the diphenol monomericunit of Formula II.

Hence, in some embodiments, the other monomer unit is the same diphenolmonomer wherein the phenyl ester moiety is replaced by, for example, afree carboxylic acid, an alkyl ester, an alkylaryl ester, an amide, anether-containing ester, an ester with an alkylene oxide chain and thelike. Examples of these and other diphenol monomers are described inU.S. Pat. Nos. 4,980,449; 5,099,060; 5,216,115; 5,317,077; 5,587,507;5,658,995; 5,670,602; 6,048,521; 6,120,491; 6,319,492; 6,475,477;6,602,497; 6,852,308; 7,056,493; RE37,160E; and RE37,795E; as well as inU.S. Patent Application Publication Nos. 2002/0151668; 2003/0138488;2003/0216307; 2004/0254334; 2005/0165203; and in PCT Publication Nos.WO99/52962; WO01/49249; WO01/49311; WO03/091337 and in U.S. Ser. No.60/733,988, filed Nov. 3, 2005.

In accordance with various embodiments of the invention, the A moiety ofthe diphenol monomer in Formula II can be selected from a number ofdifferent groups to provide a variety of polymer classes.

When A is a carbonyl group, —C(O)—, then the polymers arepolycarbonates. These polymers can be prepared by reaction with phosgeneby methods known to those of skill in the art, including those describedin U.S. Pat. No. 5,099,060. When A is —C(O)—R₁—C(O)—, then A, taken withthe oxygens in the backbone, forms a diacid (i.e., these diacid-basedester groups present in the backbone, when hydrolyzed, form a diacid).For simplicity, A is sometimes referred to herein as a diacid (thoughthis is clearly not strictly in keeping with the actual definition of Aas used in the claims but is clear in context).

When A is a diacid, the polymers are polyarylates. For thesepolyarylates (as well as other polymers of the invention), R₁ is adivalent hydrocarbon group and can be linear or branched, substituted orunsubstituted. Such groups include alkyl, alkenyl, aryl, alkylarylmoieties having from 1 to 30 carbon atoms as well as larger alkyleneoxide or arylene oxide moieties (based on the number of repeating unitsin those groups. As an example, when R₁ is an alkylene oxide, that groupcan be represented by the formula —(R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r),(with a, r, s, R₂, R₃ and R₄ as defined above which includespolyethylene glycol chains (PEG) such as —CH₂O(CH₂CH₂O)_(s)CH₂— or—CH₂CH₂O(CH₂CH₂O)_(s)CH₂CH₂— and polypropylene glycol chains such as—CH₂CH₂CH₂O(CH₂CH₂CH₂O)_(s)CH₂CH₂CH₂— and the like. Likewise, R₁ can berepresented by the formula —(R₂)_(r)CO₂((CR₃R₄)_(a)O)_(s)CO(R₂)_(r). Ina specific embodiment, this formula provides polymers which have PEGbis-succinate groups as A. for PEG bis-succinate, A is represented bythe formula—C(O)CH₂CH₂C(O)O(CH₂CH₂O)_(s)C(O)CH₂CH₂C(O)—,

where both R₂s are ethylene and R₃ and R₄ together form an ethylenegroup. If the formula is the same except that both R₂s are n-propylene,then the A moiety would be a PEG bis-glutarate.

In particular embodiments, the diacids formed by A include oxalic acid,malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid,suberic acid, azelaic acid, and sebacic acid, as well as diglycolic acid(where R₁ is —CH₂OCH₂—), dioxaoctanoic acid (R₁ is —CH₂OCH₂CH₂OCH₂—),alkylene oxide derivatives such as PEG, PEG bis-succinate and the like.

Methods of making polyarylates are known in the art. Such methods arefound, for example, in U.S. Pat. Nos. 5,216,115; 5,317,077; 5,587,507;5,670,602; 6,120,491; RE37,160E; and RE37,795E as well as in theliterature, other patents and patent applications. Those of skill in theart can readily adapt these procedures to synthesize the polymers of thepresent invention.

When A is an imino group, —C(═NH)—, then the polymers arepolyiminocarbonates. Polyiminocarbonates in general, and methods oftheir synthesis are described, e.g., in U.S. Pat. Nos. 4,980,449 and5,099,060.

When A is —C(O)—N—R₁—NH—C(O)—, then the polymers of the invention arepolyurethanes. Polyurethanes can be prepared as known in the art, forexample, by a condensation reaction between a diol and a diisocyanate ofthe formula O═C═N—R₁—N═C═O to produce polyurethanes of the invention.The R₁ group is as defined hereinabove.

When A is a thionyl group, —C(S)—, then the polymers of the inventionare polythiocarbonates. These polymers can be prepared, for example, byreaction with thiophosgene by methods known to those of skill in theart.

In accordance with various embodiments of the invention, the B moiety ofthe diphenol monomer in Formula II is a trivalent, linear or branched,substituted or unsubstituted alkyl, alkenyl, aryl or alkylaryl moietyhaving 1-20 carbon atoms. Any of the foregoing groups can contain one ormore heteroatoms in the hydrocarbon chain or group such as O, N or S.Moreover, the substituents on the hydrocarbon chain or group can haveheteroatoms as part of the substituents, such as provided by —CF₃,—CH₂F, —NO₂ and the like. In one embodiment of the invention B is

with R₇ and R₈ as defined herein and the CH bond is attached to thecarboxyl of Formula II When R₇ and R₈ are both ethylene, then the Bmoiety taken with the diphenol rings, form the backbone portion ofdes-aminotyrosyltyrosine, which with a carboxyl group (—C(O)OH) attachedto the CH group, is the free acid form of des-aminotyrosyltyrosine. Inpreferred embodiments, R₇ is independently a bond, a methylene or anethylene group, and R₈ is independently a bond, a methylene or anethylene group.

In accordance with various embodiments of the invention, each backbonearomatic ring of Formula II can have from zero to four Z₁ or Z₂substituents. If the valence of a position on the aromatic ring, is nototherwise filled, then that position has a hydrogen atom. Z₁ or Z₂ areeach independently selected from the group consisting of a halide, alower alkyl, an alkoxy, a nitro, an alkylether, a protected hydroxyl, aprotected amino and a protected carboxylic acid group.

When at least one of Z₁ or Z₂ is present and is bromine or iodine, thenthe polymer is radioopaque and has the uses described in U.S. Pat. No.6,475,477. For example, use of radioopaque medical devices allowsnon-invasive techniques to monitor the presence and/or disappearance ofthe device, including the biodegradation and resorption of the device.Similarly, radioopaque microspheres formed from polymers of theinvention may be useful as imaging agents or for drug delivery, andagain can be monitored with non-invasive techniques such as x-ray, CATscan, and the like.

Such polymers can be prepared from diphenol monomers units that havebeen halogenated prior to polymerization using standard halogenationreactions. While such reactions may tend to have preferred positions forthe halogen atom on the aromatic ring (e.g., ortho), it is contemplatedthat the halogen atom can be at any available position.

In accordance with various embodiments of the invention, the pendantphenyl ring of Formula I and II has from zero to five R substituents onthe phenyl ring and these substituents can be at any position. When no Rgroup is present, then the ester of the polymer is an unsubstitutedphenyl ester. When one R group is present, that R group is more readilyadded at the 2 or the 4 position (ortho or para). When two R groups arepresent, those R groups are generally at the 2 and 4 positions, but canalso be at the 3 and 5 positions.

Accordingly, each R moiety when present on the pendant phenyl ring isindependently linear or branched, substituted or unsubstituted,saturated or unsaturated alkyl, aryl, alkylaryl, heteroatom-containingalkyl or aryl, alkylcycloalkyl, alkoxy, aryloxy or alkylether havingfrom 1 to 20 carbon atoms; halide; nitro;—(R₂)_(r)O((CR₃R₄)_(a)O_(s)—R₅; —O((CR₃R₄)_(a)O)_(s)—R_(s); —C(O)—YR₆; aprotected hydroxyl group; a protected amino group or a protectedcarboxylic acid group.

When R is a substituted alkyl group, in addition to the other groupsrecited above in the definitions section, the substituents also beselected from —CX₃, —CHX₂, —CH₂X, —R₂CX₃, —R₂CHX₂ and —R₂CH₂X, wherein Xis a halogen (F, Cl, I or Br) and R₂ is a lower alkylene or alkenylenegroup as defined herein. These groups thus include, trifluoromethyl,trifluoroethyl and the like. For example, if R is —R₂CX₃, R₂ is —CH₂—and X is F, then the R group is trifluoroethyl. For these substituents,preferred X is F or Cl and preferred R₂ is methylene or ethylene.

When R is an alkylaryl group, in addition to the other groups recitedabove in the definitions section, the alkylaryl group can be a tritylgroup.

When R is a heteroatom-containing alkyl group, in addition to the othergroups recited above in the definitions section, that group can betrimethyl silane or N-hydroxysuccinimide.

When R is alkoxy, a preferred alkoxy group is —OCH₃.

R can also be represented by the formula —(R₂)_(b)C(O)—YR₆ where b iszero or one, Y is oxygen or nitrogen (i.e., O or N) and R₂ and R₆ are asdefined herein. When Y is —O—, then the R group, taken as a whole, canbe a free acid or an ester of benzoic acid, phenyl acetic acid,desaminotyrosine and the like. The preferred R₆ groups are hydrogen,methyl, ethyl, propyl, butyl (including t-butyl) and benzyl. By way ofexample, when b is zero, and R₆ is not hydrogen, the substituents areparabens, that is benzoic acid esters. In another example, when b is oneand R₂ is methylene, the substituents are phenylacetic acid derivatives.When b is one and R₂ is ethylene, the substituents are desaminotyrosinederivatives, and if R₂ is ethenylene, the substituents are cinnamic acidderivatives.

The parabens are particularly useful phenyl ester groups, especiallymethyl paraben (MB), ethyl paraben (EB) and propyl paraben (PB). Anotheruseful group is the ethyl ester of desaminotyrosine (DATE) as well asthe corresponding free acid and methyl, propyl, t-butyl, and benzylesters of desaminotyrosine.

When Y is —NH—, then the R group, taken as a whole, can be a free amineor an amide of benzoic acid, phenyl acetic acid, desaminotyrosine andthe like. The preferred R₆ groups are hydrogen, methyl, ethyl, propyl,butyl (including t-butyl) and benzyl. By way of example, when b is zero,and R₆ is not hydrogen, the substituents are benzamides. In anotherexample, when b is one and R₂ is methylene, the substituents arephenylacetamides. When b is one and R₂ is ethylene, the substituents areamides related to desaminotyrosine, and if R₂ is ethenylene, thesubstituents are cinnamides.

When R is an alkylene oxide, that group can be represented by theformula —(R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), (with a, r, s, R₂, R₃ andR₄ as defined above) which includes polyethylene glycol chains (PEG)such as —CH₂O(CH₂CH₂O)_(s)CH²— or —CH₂CH₂O(CH₂CH₂O)_(s)CH₂CH₂— andpolypropylene glycol chains such as—CH₂CH₂CH₂O(CH₂CH₂CH₂O)_(s)CH₂CH₂CH₂— and the like. Likewise, R₁ can berepresented by the formula —(R₂)_(r)CO₂((CR₃R₄)_(a)O)_(s)CO(R₂)_(r). Ina specific embodiment, this formula provides polymers which have PEGbis-succinate groups as A, namely A can be represented by the formula—C(O)CH₂CH₂C(O)O(CH₂CH₂O)_(s)C(O)CH₂CH₂C(O)—,

where both R₂s are ethylene and R₃ and R₄ together form an ethylenegroup. If the formula is the same except that both R₂s are n-propylene,then the A moiety would be a PEG bis-glutarate.

R can also be a protected hydroxyl, protected amine or protectedcarboxylic group. In addition to the uses of the invention, in someinstances, polymers having such protected substituents can be used asintermediates to prepare other polymers of the invention. Protectinggroups for OH, NH₂ and COOH groups are well known in the art and any aresuitable for use in accordance with various embodiments of theinvention, provided they are stable and compatible with the syntheticmethods used to produce the polymers of the invention.

The R₁ is part of the A moiety of Formula II and has been describedabove. In particular, R₁ appears as part of the diacid moiety of A,i.e., as —C(O)—R₁—C(O)—, or as part of the urethane moiety, i.e., as—C(O)—NH—R₁—NH—C(O)—.

R₂, is independently a linear or branched lower alkylene or akylenylenegroup. In preferred embodiments, R₂ is methylene, ethylene or propylene.

When present in the group —(R₂)_(r)O((CR₃R₄)_(a)O)_(s)(R₂)_(r), each R₃and R₄ is independently a hydrogen or a linear or branched lower alkylgroup. For example, if R₃ and R₄ are both hydrogen and a is 2, then thatmoiety is ethylene. Hence taken together and in combination with thevalue of a, R₃ and R₄ form a divalent alkyl groups, including but notlimited to such as methylene, ethylene, propylene, butylene and thelike.

In accordance with various embodiments of the invention, R₅ isindependently linear or branched, substituted or unsubstituted,saturated or unsaturated alkyl. Preferred alkyl groups include methyl,ethyl, propyl, butyl (t-butyl, n-butyl, isobutyl) and the like.

R₆ has been described above and is part of the formula—(R₂)_(b)C(O)—YR₆. The preferred R₆ groups are hydrogen, methyl, ethyl,propyl, butyl (including t-butyl) and benzyl.

R₇ and R₈ have been described above and are each independently a bond,or linear or branched, substituted or unsubstituted alkyl, alkenyl oralkynyl having from 1 to 20 carbon atoms. When substituted, thesubstituent can be any of those described herein as well as —X, —CX₃,—CHX₂, —CH₂X, —NHR₉, or —NHC(O)R₁₀, provided that they are compatiblewith the chemistry needed to synthesize the polymer.

R₉, when present forms part of an amino group, is a linear or branched,substituted or unsubstituted, saturated or unsaturated alkyl, aryl oralkylaryl group or an amino protecting group.

R₁₀, when present forms part of an amide linkage and is a linear orbranched alkyl, aryl or alkylaryl group.

The values of each a is independently one of the whole numbers 1, 2, 3or 4. The value of each b is independently zero or one. When b is zero,the corresponding group is omitted and a single carbon bond is present.The value of each r is independently one of the whole numbers 1, 2, 3 or4.

The value of each s is independently about 1 to about 5000 anddetermines the number of repeat units in the alkylene oxide chain.Hence, s can range from 1 to about 10, to about 15, to about 20, toabout 30, to about 40, to about 50, to about 75, to about 100, to about200, to about 300, to about 500, to about 1000, to about 1500, to about2000, to about 2500, to about 3000, to about 4000 and to about 5000.Additionally, when the length of the alkylene oxide chain is related asa molecular weight, such as with PEG 200, PEG 400, PEG 600 and the like,then s need not be a whole number but can also be expressed as afractional value, representative of the average number of alkylene oxiderepeating units based on the cited (or a measured) molecular weight.

One group of preferred polymers of the invention are polyarylates inwhich the diphenol monomer unit of Formula II is selected such that

A is —C(O)—R₁—C(O)—;

B is

R₁ is, independently, a divalent, linear or branched, substituted orunsubstituted alkyl having from 1 to 30 carbon atoms; —(R₂)_(r),O((CR₃R₄)_(a)O)_(s)(R₂)_(r); or —(R₂)_(r)CO₂((CR₃R₄)_(a)CO(R₂)_(r);

each R₂ is independently linear or branched, lower alkylene;

each R₃ and R₄ is independently hydrogen or linear lower alkyl; and

R₇ and R₈ are each independently a bond, or linear or branched alkylhaving from 1 to 20 carbon atoms.

Examples of polymers of the invention include, but are not limited to,

poly(desaminotyrsosyl tyrosine methylparaben ester glutarate), alsoreferred to as poly(DTMB glutarate);

poly(4-hydroxy-benzoic acid tyrosine methylparaben ester glutarate),also referred to as poly(BTMB glutarate);

poly(desaminotyrosyl tyrosine methylparaben ester succinate), alsoreferred to as poly(DTMB succinate);

poly(4-hydroxy-benzoic acid tyrosine methylparaben ester succinate),also referred to as poly(BTMB succinate);

poly(desaminotyrsosyl tyrosine propylparaben ester succinate), alsoreferred to as poly(DTPB succinate).

poly(4-hydroxy-benzoic acid tyrosine propylparaben ester succinate),also referred to as poly(BTPBsuccinate);

poly(desaminotyrsosyl tyrosine propylparaben ester glutarate), alsoreferred to as poly(DTPBglutarate).

poly(desaminotyrosyl tyrosine methylparaben ester-co-10% desaminotyrosyltyrosine glutarate), also referred to as poly(DTMB-co-10DT glutarate);

poly(desaminotyrosyl tyrosine methylparaben ester-co-10% desaminotyrosyltyrosine succinate), also referred to as poly(DTMB-co-10DT succinate);

poly((4-hydroxy-benzoic acid tyrosine methylparaben ester-co-15%(4-hydroxy-benzoic acid tyrosine glutarate), also referred to aspoly(BTMB-co-1 OBT glutarate);

poly((4-hydroxy-benzoic acid tyrosine methylparaben ester-co-15%(4-hydroxy-benzoic acid tyrosine succinate), also referred to aspoly(BTMB-co-10BT succinate);

poly(desaminotyrsosyl tyrosine DATE ester glutarate), also referred toas poly(DT(DATE)glutarate);

poly(desaminotyrsosyl tyrosine DATE ester glutarate), also referred toas poly(DT(DATE)glutarate); and

poly(desaminotyrsosyl tyrosine DATE ester succinate), also referred toas poly(DT(DATE)succinate).

The structure of poly(DT(DATE)succinate) is shown below:

Synthesis:

The compounds of the invention can be synthesized by a variety ofmethods using techniques known in the polymer chemistry art. In onemethod, the first step is preparation of the monomer unit with thedesired pendant phenyl ester followed by polymerization of the monomerunit to produce a polymer of the invention.

For example, if the monomer unit used in the polymerization step is adiol (e.g., to form a polyester, polyesteramide, polyarylate or othersuch polymer), the hydroxyl groups are protected while the phenyl esterderivative is prepared. To do this one can begin with the diol monomerwith a pendant carboxyl group derivatized with a relatively stable estergroup (e.g., an alkyl group such as methyl or ethyl). The diols are thenprotected with a protecting group under conditions in which ester isstable. The ester is converted to the free acid with hydrolyzing thediol protecting groups. The free acid can be reacted with a hydroxyarylcompound to produce the monomer unit bearing a phenyl ester. The diolprotecting groups are removed under conditions that do not affect thestability of the phenylester, and the resulting monomers can bepolymerized. A similar strategy can be used for other polymers with freeamines or other reactive polymerization groups.

By way of an example, desaminotyrosyl tyrosine methyl ester (DTM) isreacted with benzylbromide to produce bis-benzyl-DTM which is convertedto the free acid form, bis-benzyl-DT. That free acid is reacted withmethylparaben to produce bis-benzyl-DTMB. After debenzylation, oneobtains DTMB, which can then be polymerized by methods know in the art.

In an alternative method, polymers containing pendant phenyl esters canbe prepared in a three step process. In the first step, a precursorpolymer containing a protected pendant group is prepared. In the nextstep, the pendant protecting group is removed without degrading thepolymer backbone. In the final step, the phenyl ester is attached to thepolymer backbone, via the unprotected functionality. In general thepolymer with pendant free carboxylic acid groups is synthesized in a twostep process by polymerizing monomer units having a protecting group onthe carboxylic acid, e.g., an alkyl ester, a benzyl ester, or any otherprotecting group such as those used in peptide chemistry, followed byremoval of the protecting group without backbone degradation to yieldthe free acid-containing precursor polymer. That polymer is thenderivatized with a phenol compound (i.e., the desired hydroxyarylcompound) to produce a polymer of the invention.

For example, a tyrosine-derived polyarylate with a phenyl ester sidechain can be prepared by reacting equimolar amounts of the desireddiphenol monomer that has a benzyl ester side chain (e.g.,desaminotyrosyl tyrosine benzyl ester) and the desired diacid (e.g.,succinic acid) in an organic solvent (e.g., a chlorinated solvent suchas methylene chloride) in the presence of the catalystdimethyaminopyridinium-para-toluenesulfonate (DPTS). Once the compoundsare dispersed in the solvent, a coupling agent, such asdiisopropylcarbodiimide (DIPC), is added in molar excess and thereaction is allowed to proceed until the mixture becomes viscous,typically at room temperature. The benzyl protected polymer can beisolated by repeated precipitation from non-solvent and dried.

One method to remove the benzyl protecting group, is to dissolve thepolymer in organic solvent and bubble nitrogen through the solution fora time sufficient to remove all oxygen. A palladium catalyst such asPd/BaSO₄ is added after stopping the nitrogen. Hydrogen gas is thenpassed through the reaction mixture which is stirred overnight or untilthere is no benzyl remaining on the polymer. The completion of thehydrogenation reaction can be monitored by techniques known to those ofskill in the art such as NMR, HPLC or gas phase chromatography. Othermethods of hydrolysis, such as differential acid hydolysis, can be usedto remove the protecting group on the pendant carboxyl group providedthat the backbone of the polymer remains intact, i.e., does not degradeor does not significantly degrade, under the reaction conditions. Thefree carboxylic acid-containing polymer can be isolated by knowntechniques, preferably, e.g., by precipitation, with drying to constantweight.

The free acid polymer is dissolved in organic solvent, and a slightmolar excess of the desired phenolic compound is added if every positionis to be derivatized to a phenyl ester. To produce a polymer with aparticular percentage of free acid, the amount of the phenolic compoundis reduced by the desired percent of free acid. For example to prepare apolymer with 80% methyl paraben and 20% free acid (i.e., DTMB-20-DTglutarate), a slight excess over 0.8 mole equivalents of 4-hydroxymethyl paraben is used in the reaction. A slight molar excess can bedetermined empirically to obtain the desired percentage substitution inthe final polymer preparation; typically about 5-10% molar excess issufficient. After mixing the reactants, the mixture is cooled, asuitable coupling agent such as DIPC is added, and stirring continueduntil the reaction is complete. The final polymer is isolated, e.g., byaqueous precipitation, filtered and dried to constant weight.

Polymers of the invention can be purified by methods known to those ofskill in the art, such as by precipitation, by chromatography and thelike.

Monomers:

The present invention is also directed to diphenol monomers havingpendant phenyl ester groups. The monomers of the invention are useful asintermediates to prepare the polymers of the present invention and arerepresented by Formula III or IV

wherein

B is a trivalent, linear or branched, substituted or unsubstitutedalkyl, alkenyl, aryl or alkylaryl moiety having 1-20 carbon atoms, or is

each backbone aromatic ring has from zero to four Z₁ or Z₂ substituents,each of which is independently selected from the group consisting ofhalide, lower alkyl, alkoxy, nitro, alkylether, a protected hydroxylgroup, a protected amino group and a protected carboxylic acid group;

the pendant phenyl ring has from zero to five R substituents at anyposition on the phenyl ring, and each R is independently linear orbranched, substituted or unsubstituted, saturated or unsaturated alkyl,aryl, alkylaryl, heteroatom-containing alkyl or aryl, alkylcycloalkyl,alkoxy, aryloxy or alkylether having from 1 to 20 carbon atoms; halide;nitro; —(R₂)_(r)C((CR₃R₄)_(a)O)_(s)—R₅; —O((CR₃R₄)_(a)O)_(s)—R₅;—C(O)—R₅; —(R₂)_(b)C(O)—YR₆; a protected hydroxyl group; a protectedamino group or a protected carboxylic acid group;

each R₂ is independently linear or branched, lower alkylene or loweralkenylene;

each R₃ and R₄ is independently hydrogen, or linear or branched loweralkyl;

R₅ is independently linear or branched, substituted or unsubstituted,saturated or unsaturated alkyl;

R₆ is hydrogen; saturated or unsaturated alkyl, aryl or alkylaryl havingfrom 1 to 20 carbon atoms; or —(R₂)_(r)O((CR₃R₄)_(a)O)_(S)—R₅;

R₇ is independently a bond, or linear or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl having from 1 to 20 carbonatoms, and when substituted, the substituent can be, but is not limitedto, —X, —CX₃, —CHX₂, —CH₂X, —NHR₉, or —NHC(O)R₁₀;

R₈ is independently a bond or linear or branched, substituted orunsubstituted alkyl, alkenyl or alkynyl having from 1 to 20 carbonatoms, and when substituted, the substituent can be, but is not limitedto, —X, —CX₃, —CHX₂, —CH₂X, —NHR₉, or —NHC(O)R₁₀;

R₉ is a linear or branched, substituted or unsubstituted, saturated orunsaturated alkyl, aryl or alkylaryl group or an amino protecting group;

R₁₀ is a linear or branched alkyl, aryl or alkylaryl group;

P is an —OH protecting group;

X is a halogen;

Y is —O— or —NH—;

each a is independently 1 to 4;

each b is independently zero or one;

each r is independently 1 to 4; and

each s is independently 1 to 5000.

The embodiments of, and preferred embodiments for, B, R₂, R₃, R₄, R₅,R₆, R₇, R₈, R₉, R₁₀, X and Y are as described above in the polymersection. The values, including the preferred values, for a, b, r and sare as described above in the polymer section.

As used herein, P is a protecting group for the hydroxyls on thediphenol (backbone) rings of the monomer. Such protecting groups arestable under the chemical conditions needed to remove an alkyl ester (orother carboxylic acid protecting group) from the position occupied bythe phenyl ester (and thereby make the free acid equivalent of thesemolecules). Such protecting groups are also stable under the chemicalconditions needed to react a hydroxyaryl compound with the protectedmonomer and thereby produce a protected monomer bearing a phenyl estermoiety as shown. Finally the protecting groups can be removed from themonomer under conditions which do not cause hydrolysis of the phenylester. Benzyl is a suitable protecting group, but many others are knownin the art, see, e.g., T. W. Greene and P. G. M. Wuts, Protecting Groupsin Organic Synthesis, 3rd ed., John Wiley & Sons, Inc., New York, 1999.

Uses

The polymers of the invention are biocompatible, biodegradable polymerscomprising monomer units with pendant phenyl ester (PE) groups, i.e., PEside chains relative to the polymer backbone. The PE groups are goodleaving groups under physiological conditions and thus provide a meansto generate free pendant carboxylic moieties in vivo which leads torapid breakdown and resorption of the polymer. With the polymer beingdriven to breakdown more quickly into more water-soluble constituents,the result is faster resorption in use, especially when compared to asimilar polymer with alkyl esters replacing the equivalent amount ofphenyl esters.

For example, desaminotyrosyltyrosine ethyl ester succinate resorbs inabout 1 year but when the ethyl ester is replaced by a paraben ester,the resorption time is less than 3 months.

Breakdown of the polymer can be measured in a variety of ways. The invivo degradation process can be mimicked in vitro in several ways. Byaging a polymer-coated device (or a composition or device formedprimarily from a polymer of the invention) at 37° C. in phosphatebuffered saline at pH 7.4, the hydrolytic processes may be reproduced.If oxidative mechanisms are relevant then the same solution may besupplemented with oxidants such as hydrogen peroxide or superoxidesalts. Additionally, if enzymatic degradation processes are important,representative enzymes can be added to the solution. It is to beunderstood that while such in vitro tests can mimic the chemicalprocesses operant in vivo, they predict kinetics and rates inaccurately.Further, as needed, in vivo animal models can be used to correlate invivo and in vitro degradation behavior.

In addition to measuring polymer degradation and resorption, those ofskill in the art can monitor drug release using the same techniques aswell as others. For example, antibiotic activity can be measured by zoneof inhibition assays, pain relief can be measured in animal models forpain and more.

The polymers of the invention are relatively more hydrophobic beforebreakdown, and this provides a useful ability to solublize drugs or actas a reservoir for a wide variety of drugs, in addition to being able tomanipulate the drug release profile. Since a variety of substituents canbe used on the polymers, such as PEGs, hydrophobic groups and manyothers, the polymer can be readily manipulated for purposes of both drugformulations and for controlled or sustained release. Those of skill inthe art can thus manipulate the chemical constituents of the polymers toachieve particular release profiles for compositions, for coated devicesor for resorbable devices (whether fully or partially resorbable)—in thecontext of the faster resorption times provided by the polymers of theinvention.

Hence, the polymers of the invention have a myriad of biological useswhen a biocompatible, biodegradable polymer is needed, for coatingmedical devices, to form fully or partially resorbable medical devices,to deliver drugs in specific manners (either in conjunction with suchdevice or as part of a pharmaceutical composition comprising thepolymer, a drug and other agents). It should be understood that thepolymers are useful without the presence of drugs. For example, apolymer coating on a surgical mesh can increase mesh stiffness, andthereby allow easier handling at the time of implantation yet stillprovide a mesh that softens over time and is comfortable for thepatient. Moreover, a polymer-coated, flat mesh can be formed into athree dimensional shape, and this can be useful in surgical repairs.Fully resorbable devices can be used as sutures intended to impartstrength for a period before dissolving, as temporary wound closures,such as a femoral plug, and the like.

Further uses for the polymers of the invention are described in detail,for example, in U.S. Ser. No. 11/672,929, filed Feb. 8, 2007 whichdescribes coated surgical meshes for a variety of applications; in U.S.Ser. No. 60/864,597, filed Nov. 6, 2006 which describes fully andpartially resorbable coverings, pouchs, bags and coated meshes forcardiac rhythm management devices, neurostimulators as well as for otherimplantable medical devices; and in U.S. Ser. No. 60/908,960, filed Mar.29, 2007 and in PCT/US08/58652, filed Mar. 28, 2008, for resorbablecoverings for breast implants.

The compositions of the present invention can be used to faun medicalarticles and coatings (i) that have sufficient mechanical properties forapplications that can benefit from biodegradable polymers, (ii) that canrelease agents substantially free of additional molecules derived from apolymeric carrier, (iii) that can be designed to have a predeterminedrelease rate and resorption rate; and (iv) that can be combined withdrugs that are not only bioactive and/or biobeneficial but also controla physical property and/or a mechanical property of a medical article orcoating formed from the polymer.

Blends:

An additional way to manipulate drug release and resorptioncharacteristics is to blend polymers. Accordingly, the present inventionprovides blends of the polymers of the invention with otherbiocompatible polymers, preferably other biodegradable polymers. Theseother polymers include, but are not limited to, polylactic acid,polyglycolic acid and copolymers and mixtures thereof such aspoly(L-lactide) (PLLA), poly(D,L-lactide) (PLA), polyglycolic acid[polyglycolide (PGA)], poly(L-lactide-co-D,L-lactide) (PLLA/PLA),poly(L-lactide-co-glycolide) (PLLA/PGA), poly(D, L-lactide-co-glycolide)(PLA/PGA), poly(glycolide-co-trimethylene carbonate) (PGA/PTMC),poly(D,L-lactide-co-caprolactone) (PLA/PCL) andpoly(glycolide-co-caprolactone) (PGA/PCL); poly(oxa)esters, polyethyleneoxide (PEO), polydioxanone (PDS), polypropylene fumarate, poly(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), polycaprolactone (PCL), polycaprolactone co-butylacrylate,polyhydroxybutyrate (PHBT) and copolymers of polyhydroxybutyrate,poly(phosphazene), poly(phosphate ester), poly(amino acid),polydepsipeptides, maleic anhydride copolymers, polyiminocarbonates,poly[(97.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethylenecarbonate)], poly(orthoesters), other tyrosine-derived polyarylates,other tyrosine-derived polycarbonates, other tyrosine-derivedpolyiminocarbonates, other tyrosine-derived polyphosphonates,polyethylene oxide, polyethylene glycol, polyalkylene oxides,hydroxypropylmethylcellulose, polysaccharides such as hyaluronic acid,chitosan and regenerate cellulose, and proteins such as gelatin andcollagen, and mixtures and copolymers thereof, among others as well asPEG derivatives or blends of any of the foregoing.

Using blends provides many advantages, including the ability to makepartially resorbable devices and fully resorbable devices that havevaried resorption times for parts or all of the device. For example, apartially resorbable device may increase porosity over time and thuspermit tissue in growth. Those of skill in the art can readily pickcombinations of polymers to blend and determine the amounts of eachpolymer need in the blend to produce a particular product or achieve aparticular result.

Drugs:

Any one or more drug, biological agent, or active ingredient that iscompatible with the polymers, monomers and blends of the invention canbe incorporated in, formed into or used in conjunction or combinationwith a pharmaceutical composition or a medical device coated or formedfrom the polymers, monomers or blends of the invention. Doses for suchdrugs and agents are known in the art. Hence, those of skill in the artcan determine the amount of drug or agent desired for delivery, andcalculates the amount needed for the desired application, based on sizeof the device, coating thickness, effective doses and the like.

In accordance with various embodiments of the invention, drugs andbiologically-active agents include, but are not limited to, anesthetics,antimicrobials (which include antibiotics, antifungal agents andantibacterial agents), anti-inflammatory agents, fibrosis-inhibitingagents, anti-scarring agents, cell growth inhibitors, growth factors andthe like.

As used herein, “drugs” is used to include all types of therapeuticagents, whether small molecules or large molecules such as proteins,nucleic acids and the like. The drugs of the invention can be used aloneor in combination.

Examples of non-steroidal anti-inflammatory agents include, but are notlimited to, acetominophen, aspirin, celecoxib, diclofenac, diflunisal,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meclofenamate, meloxicam, methyl salicylate, nabumetone, naproxen,oxaprozin, piroxicam, sulindac, tolmetin and trolamine.

Examples of anesthetics include, but are not limited to, lidocaine,bupivacaine, mepivacaine and xylocaine. Local anesthetics have weakantibacterial properties and can play a dual role in the prevention ofacute pain and infection.

Examples of antimicrobial drugs include, but are not limited to,

aminoglycosides such as amikacin, gentamicin, kanamycin, neomycin,streptomycin, and tobramycin;

antibiotics such as bacitracin, clindamycin, daptomycin, lincomycin,linezolid, metronid, polymyxin, rifaximin, vancomycin;

cephalosporins such as cephazolin;

macrolide antibiotics such as erythromycin, azithromycin and the like;

β-lactam antibiotics such as penicillins;

quinolones such as ciprofloxacin;

sulfonamides such as sulfadiazine;

tetracyclines such as minocycline and tetracycline; and

other antibiotics such as rifampin, triclosan, chlorhexidine, sirolimusand everolimus.

Other drugs that can be used include, but are not limited to, keflex,acyclovir, cephradine, malphalen, procaine, ephedrine, adriamycin,daunomycin, plumbagin, atropine, quinine, digoxin, quinidine,biologically active peptides, cephradine, cephalothin,cis-hydroxy-L-proline, melphalan, penicillin V, nicotinic acid,chemodeoxycholic acid, chlorambucil and anti-neoplastic agents such aspaclitaxel, sirolimus, 5-flurouracil and the like. Examples of usefulproteins include cell growth inhibitors such as epidermal growth factorantagonists.

Preferred antimicrobial agents of the invention include rifampin,minocycline, gentamicin, vancomycin, triclosan, sirolimus andeverolimus, alone or in combination. Rifampin and minocyline are apreferred combination of anti-microbial agents.

Leukotriene inhibitors/antagonists are anti-inflammatory agents andinclude, but are not limited to, leukotriene receptor antagonists suchas acitazanolast, iralukast, montelukast, pranlukast, verlukast,zafirlukast, and zileuton.

Pharmaceutical Formulations:

The polymers and blends of the invention can be formulated aspharmaceutical compositions comprising one or more of those molecules,one or more drugs (as active ingredient), and a pharmaceuticallyacceptable carrier. Pharmaceutically acceptable carriers can be sterileliquids, such as water and oils, including those of petroleum, animal,vegetable or synthetic origin, such as peanut oil, soybean oil, mineraloil, sesame oil and the like. Water is a preferred carrier when thepharmaceutical composition is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid carriers, particularly for injectable solutions.Suitable pharmaceutical carriers are well known. In addition to thepharmacologically active agent, the compositions can contain suitablepharmaceutically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically for delivery to the siteof action. Suitable formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form, forexample, water-soluble salts. In addition, suspensions of the activecompounds, as appropriate in injection suspensions may be administered.Suitable lipophilic solvents or vehicles include fatty oils, forexample, sesame oil or synthetic fatty acid esters, for example, ethyloleate or triglycerides. Aqueous injection suspensions can containsubstances which increase the viscosity of the suspension include, forexample, sodium carboxymethyl cellulose, sorbitol, and dextran.Optionally, the suspension can also contain stabilizers. Liposomes canalso be used to encapsulate the agent for delivery into cells.

The pharmaceutical formulation for systemic administration according tothe invention can be formulated for enteral, parenteral or topicaladministration. Indeed, all three types of formulations can be usedsimultaneously to achieve systemic administration of the activeingredient.

Suitable formulations for oral administration include hard or softgelatin capsules, pills, tablets, including coated tablets, elixirs,suspensions, syrups or inhalations and controlled release forms thereof.

The polymers and blends of the invention can also be incorporated intopharmaceutical compositions which allow for the sustained delivery ofthose compounds to a mammal for a period of several days, to at leastseveral weeks, to a month or more. Such formulations are described inU.S. Pat. Nos. 5,968,895 and 6,180,608 B1.

For topical administration, any common topical formation such as asolution, suspension, gel, ointment or salve and the like can beemployed. Preparation of such topical formulations are well described inthe art of pharmaceutical formulations as exemplified, for example, byRemington's Pharmaceutical Sciences. For topical application, thepolymers and blends of the invention can also be administered as apowder or spray, particularly in aerosol form. The active ingredient canbe administered in pharmaceutical compositions adapted for systemicadministration. As is known, if a drug is to be administeredsystemically, it can be confected as a powder, pill, tablet or the likeor as a syrup or elixir for oral administration. For intravenous,intraperitoneal or intra-lesional administration, the active ingredientcan be prepared as a solution or suspension capable of beingadministered by injection. In certain cases, it may be useful toformulate the active ingredient in suppository form or as an extendedrelease formulation for deposit under the skin or intramuscularinjection. In a one embodiment, the polymers and blends of the inventionmay facilitate inhalation therapy. For inhalation therapy, the polymersor blends together, with the active ingredient, can be in a solutionuseful for administration by metered dose inhalers or in a form suitablefor a dry powder inhaler.

Medical Devices:

The polymers and blends of the invention can be used to coat or formimplantable prostheses used to reconstruct, reinforce, bridge, replace,repair, support, stabilize, position or strengthen any soft tissuedefect. For example, soft tissue defects that can be treated inaccordance with various embodiments of the instant invention includinghernias, such as but not limited to inguinal, femoral, umbilical,abdominal, incisional, intramuscular, diphragmatic, abdomino-throacicand thoracic hernias. The prosetheses can also be used for structuralreinforcement for muscle flaps, to provide vascular integrity, forligament repair/replacement and for organsupport/positioning/repositioning such as done with a bladder sling, abreast lift, or an organ bag/wrap. The prosetheses can be used inrecontruction procedures involving soft tissue such as an orthopaedicgraft support/stabilization, as supports for reconstructive surgicalgrafts and as supports for bone fractures.

The prostheses are generally meshes, membranes or patches, and includewoven or non-woven meshes and the like.

Additionally, the polymers and blends of the invention can be used tocoat or to form wound closure adjuncts, such as staples, sutures, tacks,rings, screws, and the like.

The polymers and blends of the invention can also be used to coat mesheswhich are formed into or to form pouches, coverings, pockets and thelike for implantable medical devices. Such implantable medical devicesinclude, but are not limited to cardiac rhythm management devices suchas a pacemaker, a defibrillator, a pulse generator as well as otherimplantable devices such as implantable access systems,neurostimulators, spinal cord stimulators, breast implants or any otherimplantable medical device. The coverings, pouches, pockets and the likehence can serve to secure those devices in position, provide painrelief, inhibit scarring or fibrosis, inhibit or prevent bacterialgrowth or infection, and deliver other drugs to the site ofimplantation.

The polymers and blends of the invention can also be used in conjunctionwith any implantable or insertable medical devices which has atemporary, or some time-limited therapeutic need as well as those withpermanent function (such as joint replacements). For example, suchpolymers can be used to form fully resorbable vascular stents, whichafter a sufficient period of healing become completely resorbed whileleaving a, patent blood vessel. Fully resporbable stents may be used inconjunction with one or more drugs.

More detail and other examples of medical devices to which the presentpolymers and blends are useful include, but are not limited to,catheters (e.g., renal or vascular catheters such as balloon catheters),guide wires, balloons, filters (e.g., vena cava filters), stents(including coronary vascular stents, cerebral, urethral, ureteral,biliary, tracheal, gastrointestinal and esophageal stents), stentgrafts, cerebral aneurysm filler coils (including Guglilmi detachablecoils and metal coils), vascular grafts, myocardial plugs, femoralplugs, patches, pacemakers and pacemaker leads, heart valves, vascularvalves, biopsy devices, patches for delivery of therapeutic agent tointact skin and broken skin (including wounds); tissue engineeringscaffolds for cartilage, bone, skin and other in vivo tissueregeneration; sutures, suture anchors, anastomosis clips and rings,tissue staples and ligating clips at surgical sites; orthopedic fixationdevices such as interference screws in the ankle, knee, and hand areas,tacks for ligament attachment and meniscal repair, rods and pins forfracture fixation, screws and plates for craniomaxillofacial repair;dental devices such as void fillers following tooth extraction andguided-tissue-regeneration membrane films following periodontal surgery;and various coated substrates that are implanted or inserted into thebody.

Use of the polymers and blends with any of the medical devices describedherein can include can be used with one or more drugs.

Accordingly, the present invention provides methods of treating adisorder or condition in a patient comprising implanting a medicaldevice or a medical device assembly comprising a polymer or blend of theinvention, e.g., as a coating, in conjuction with a covering or as thecomplete or partial device, by implanting the device in a patient, andparticularly for disorders and conditions such as a cardiovasculardisorder, a neurological disorder, a hernia or hernia-related disorder,an ophthalmic condition, or anatomical repair, reconstruction,replacement or augmentation.

In some embodiments, the method is used to implant a stent to treatatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation for vein andartificial grafts, bile duct obstruction, ureter obstruction, tumorobstruction, or combinations thereof.

In other embodiments, the method is used to implant a surgical mesh toreconstruct, reinforce, bridge, replace, repair, support, stabilize,position or strengthen any soft tissue defect, including a hernia.

In yet other embodiments, the method is used to implant a medical deviceassembly such as a CRM in a covering or pouch, a neurostimulator in apouch or covering, or a breast implant in a pouch or covering.

It will be appreciated by those skilled in the art that variousomissions, additions and modifications may be made to the inventiondescribed above without departing from the scope of the invention, andall such modifications and changes are intended to fall within the scopeof the invention, as defined by the appended claims. All references,patents, patent applications or other documents cited are hereinincorporated by reference in their entirety for all purposes.

Example 1 Synthesis of Poly(desaminotyrsosoyl tyrosine methylparabenester glutarate)

A. Preparation of poly(DTBn-glutarate)

DTBn (0.5 mol, 209.66 g), glutaric acid (0.5 mol, 66.06 g), DPTS (0.2mol, 58.84 g) were placed in a 3 L flask equipped with an overheadstirrer and condenser. Methylene chloride (1.2 L) was added to the flaskand the contents stirred until all the solids were dispersed. DIPC (1.5mol, 189.3 g, 234.2 mL) was added and stirring continued for 20-22 h bywhich time reaction mixture was viscous. The polymer was isolated byrepeated precipitations from methylene chloride and isopropanol (IPA).The solid polymer was transferred to a polypropylene tray and left todry in the hood overnight, transferred to a vacuum oven at 50° C. anddried to constant weight. The yield of poly(DTBn-glutarate) was 203 g(76%). The polymer had a molecular weight of 100 kDa and a T_(g) of 66°C.

B. Removal of Pendant Benzyl Esters to Produce poly(DT-glutarate)

A 5% solution of poly(DTBn-glutarate) was prepared by dissolving 200 gof the polymer in 4 L dimethylformamide (DMF). Nitrogen was bubbledthrough the clear solution for about 30 minutes. While stirring, 54 g ofcatalyst (5% Pd on BaSO₄; 27% w/w with respect to the benzyl precursorpolymer) was added all at once. Hydrogen gas was bubbled through thesolution and stirring continued overnight. The reaction mixture wasfiltered on a Celite bed (celite is a diatomaceous filter aid) and thede-benzylated polymer was precipitated in cold water. The wet polymercake was dried to constant weight under vacuum. The yield ofpoly(DT-glutarate) was 142 g (71%). The polymer had a molecular weightof 95 kDa and a T_(g) of 111° C.

C. Addition of Methyl Paraben to Produce poly(DTMB-glutarate):

Poly(DT-glutarate) (0.0564 mol, 25 g) was dissolved in 150 mL DMF in a250 mL round-bottom flask. While stirring, p-hydroxy methyl benzoate(0.225 mol, 34.3 g) was added (Molar ratios as low as a 10% excess arealso effective). The flask was then cooled in an ice water bath.Successively, dimethylaminopyridine (DMAP) (0.55 g, 0.0045 mol) and thenDIPC (0.062 mol, 7.83 g, 9.7 mL) were added to the flask. After 15 min,the flask was removed from the ice water bath and the reaction allowedto proceed overnight. The reaction mixture was slightly viscous and wastreated with 4 mL of glacial acetic acid. The urea formed was filteredthrough a sintered funnel to obtain the clear filtrate. With stirring,the polymer-containing filtrate was added to 550 mL of solvent 9:1IPA:methanol. The precipitated polymer was washed with twice with 100 mLIPA, redissolved in 500 mL of DMF and poured into 3 L of 20% aqueousNaCl to precipitate the poly(DTMB-glutarate). The precipitated polymerwas collected on a sintered funnel under vacuum, transferred to a glassdish, dried overnight in a hood, and then dried in a vacuum oven toconstant weight. The yield of poly(DTMB-glutarate) was 17 g (52%). Thepolymer had molecular weight of 60 kDa and a T_(g) of 71° C.

Example 2 Synthesis of Poly(desaminotyrososyl tyrosine propylparabenester glutarate)

The polymer poly(desaminotyrsosyl tyrosine propylparaben esterglutarate), i.e., poly(DTPB glutarate), was synthesized as described inExample 1 except that in step C, phydroxy propyl benzoate (0.225 mol,40.5 g) was added to the solution of poly(DT-glutarate) in DMF. Theremainder of the polymer work up remained the same and yieldedpoly(DTPBglutarate) 21 g (61%). The polymer had molecular weight of 70kDa and a T_(g) of 66° C.

Example 3 Sythesis of Poly(desaminotyrosyl tyrosine methylparaben estersuccinate)

The polymer poly(desaminotyrsosyl tyrosine methylparaben estersuccinate), i.e., poly(DTMB succinate), was synthesized as described inExample 1 except that in step C, glutaric acid was replaced withsuccinic acid. The remainder of the polymer work up and synthesisgenerally remained the same and yielded poly(DTMB-succinate) 18 g (54%).The polymer had a molecular weight of 40 kDa and a T_(g) of 76° C.

Example 4 Synthesis of Poly(desaminotyrosyl tyrosine Methylparabenester-co-10% desaminotyrosyl tyrosine succinate)

To prepare a polymer with free acid monomer, the synthesis of Example 1is followed, except that in step A, succinic acid is substituted forglutaric acid and in step C, 0.9 equivalents of methylparaben is addedto poly(DT) to yield poly(DTMB-10-DT succinate).

Example 5 Synthesis of Poly(desaminotyrosyl tyrosine DATE esterglutarate)

The polymer poly(desaminotyrsosyl tyrosine DATE ester glutarate), i.e.,poly(DT(DATE) glutarate), was prepared from poly(DT glutarate) obtainedas described in Example 1, steps A and B. The ethyl ester ofdesaminotyrosyl tyrosine was prepared as described in step A below andreacted with poly(DT glutarate) as described in step B below to producethe final product, poly(DT(DATE) glutarate).

A. DATE Preparation

To prepare DATE, a solution of 3-[4-hydroxyphenyl]propionic acid (24.2g, 0.146 mol) in 300 mL of 200 proof ethanol containing 47 mL 4 MHCl/dioxane was mixed at reflux for 4 h. After distilling away much ofthe solvent, the residue was rotary evaporated at 65° C. under vacuum torender a yellow liquid (30 g). This liquid residue was dissolved in 75mL toluene and extracted twice with 3% NaHCO₃/14% NaCl (75 mL) followedonce by 75 mL 20% NaCl. The toluene solution was dried over anhydrousmagnesium sulfate and rotary evaporated to leave a further liquidresidue which was further co-evaporated with 50 mL portions of toluene.After the final evaporation, the residue was dried in a vacuum oven toyield 25 g of a moderately viscous yellow liquid with virtually no odorof toluene. TLC (silica gel with a 9:1 methylene chloride:methanolsolvent system) showed a single spot at an R_(f) of 0.50 when visualizedby UV and iodine. NMR (D₆MSO): 1.3 ppm (t, 3H), 2.5-2.9 ppm (a²b², 4H),4.1 ppm (q, 3H), 6.7-7.1 ppm (ab, 4H), 9.4 ppm (s, 1H).

B. DATE Addition to poly(DT glutarate)

The DATE prepared in step A (0.125 mol, 24.3 g) and poly(DT glutarate)(0.034 mol, 14.5 g) were dissolved in 125 mL DMF and the solution wascooled in an ice-water bath. DIPC (0.042 mol, 6.6 mL) was added to thesolution, after stirring for 5 min, DMAP (0.0028 mol, 0.34 g) was addedand stirring continued overnight in the ice bath (which was allowed tocome to room temperature during that time). The reaction mixture wasadded rapidly dropwise to 1200 mL (9:1 IPA:methanol, resulting in anelastomeric precipitate. The solvents were decanted and the solid washedtwice with 1200 mL IPA containing 0.5 mL of glacial acetic acid. Thewashed solid was dissolved in 150 mL DMF containing 1 mL glacial aceticacid, filtered and re-precipitated by rapid dropwise addition to 1800 mLdistilled water. This precipitate was resuspended twice in 1 L of colddistilled water, filtered over a polypropylene membrane and washedseveral times with distilled water before drying at 45° C. for severaldays in a vacuum oven. The poly(DT(DATE) glutarate) had a molecularweight of 82 kDa as determined by gel permeation chromatography(DMF/0.1% TFA, 0.8 mL/m, PEG standards) and a T_(g) of 43.03° C. NMR:(D₆MSO): 1.6 ppm (t, 3H), 4.1 ppm (q, 2H).

Example 6 Alternate Synthesis Route for Poly(DTMB glutarate) and Poly(DTMB succinate)

A. Monomer Preparation

A mixture of DTM (18.8 g, 0.0548 mol), potassium carbonate (16.6 g,0.1205 mol) and benzyl bromide (13.7 mL, 0.1150 mol) were refluxed in100 mL of acetone for 16 h. The reaction mixture was added to 260 mL ofdichloromethane, stirred and filtered through a fine porosity sinteredfunnel. The clarified filtrate was concentrated on a rotary evaporatorto yield a slush. The slush was diluted with 800 mL hexane and stirredto produce a smooth suspension. The solid was filtered and vacuum driedat 40° C. to yield 25 g of the bis-benzyl derivative which showed asingle R_(f) spot on silica gel TLC (9:1 methylene chloride:methanol) at0.77 when visualized by UV and iodine. NMR: 3.7 ppm (s, 1H), 4.4 ppm (m,1H), 5.1 ppm (s, 4H), 6.8-7.4 ppm (m, 18H), 8.4 ppm (d, 1H).

A mixture of bis-benzyl DTM (25.3 g) and NaOH (61.4 g) was stirred in600 mL distilled water at 95-100° C. for 20 min. The mixture was cooledin a ice bath, the pH was adjusted to 2.5 by adding 8 M HCl, andfiltered over a sintered glass funnel. The white crystalline solid wasdried under vacuum at 40° C. for 2 days, 23.7 g. Silica gel TLC (9:1methylene chloride:methanol with 1% acetic acid) showed a single spot atR_(f) 0.41 when visualized by uv and iodine. mp: 201.7° C. NMR: 4.4 ppm(m, 1H), 5.1 ppm (s, 4H), 6.87.4 ppm (m, 18H), 8.2 ppm (d, 1H), 12.7 ppm(s, 1H).

A mixture of bis-benzyl-DT (26.6 g, 0.0522 mol), methyl paraben (7 g,0.0493 mol) and DPTS (7.8 g, 0.0265 mol) was stirred in 117 mL ofN-methylpyrrolidinone for 15 min at room temperature, and thetemperature lowered to 2-5° C. in an ice-water bath. DIPC (8.8 mL,0.0562 mol) was added to the cooled solution and the mixture stirredovernight in the ice-bath (without refreshment). The mixture was kept ina freezer for 3-4 h before filtering to remove the diisopropylureasolid. The clarified filtrate was added to 3200 mL cold, distilled waterwith stirring continued overnight or until coagulation of the milkysolid was complete. The white solid product was isolated by filtrationand dried under vacuum at 40° C. The dried solid (32 g) wasrecrystallized from a solution of 470 mL ethanol (200 proof) with 90 mLof glacial acetic acid and vacuum dried at 30° C. to yield 21 g whitecrystalline product, bis-benzyl-DTMB. Silica gel TLC (9:1 methylenechloride:methanol with 1% acetic acid) showed a single spot at an R_(f)of 0.55 when visualized by uv and iodine. Methylparaben was notdetected. NMR: 2.4 ppm (m, 2H), 2.7 ppm (m, 2H), 3.1 ppm (a²b², 2H), 3.9ppm (s, 3H), 4.6 ppm (q, 1H), 5.1 ppm (s 2H), 5.2 ppm (s, 2H), 6.8-7.9ppm (m, 22H), 8.6 ppm (d, 1H).

A solution of bis-benzyl-DTMB (21.6 g) in 162 mL DMF was hydrogenatedover 7.9 g of Pd/C (10%) at atmospheric pressure for 10-12 h. Themixture was diluted with 400-500 mL of ethyl acetate and catalyst wasremoved by filtration through filter paper followed by two extractionswith 600 mL 20% NaCl, two extractions with 500 mL 3% NaHCO₃/14% NaCl andtwo extractions with 300 mL 20% NaCl. The clarified solution was driedover anhydrous magnesium sulfate and concentrated to a stiff gum in arotary evaporator. Repetitively mixing the gum with methylene chlorideand rotary evaporating to produce the gum, followed by submersion of thegum under hexane for several days led to a white crystalline solid.After filtration and vacuum drying, the yield was 12.2 g DTMB having amelting point of 132° C. Silica gel TLC (9:1 methylene chloride:methanol with 1% acetic acid) showed a major spot at an R_(f) of 0.35when visualized by UV and iodine. NMR: 2.4 ppm (m, 2H), 2.6 ppm (m, 2H),2.8 ppm (m, 2H), 3.7 ppm (s, 3H), 4.5 ppm (m, 1H), 6.6-8.0 ppm (m, 12H),8.5 ppm (d, 2H), 9.1 ppm (s, 1H), 9.3 ppm (s, 1H); elemental: % C,67.71, % H, 5.16, % N, 3.03: theory: % C, 67.38, % H, 5.44, % N, 3.02.

B. Polymerization

To form poly(DTMB glutarate) or poly(DTMB succinate), the DTMB monomeris polymerized with glutaric acid or succinic acid, respectively,according to the method described in Example 1, step A.

Example 7 In Vivo Mass Loss Studies

To analyze the mass loss and degradation profile, polypropylene meshwhich had been laser cut into small pieces was dip coated with theindicated polymer to provide an average of 3-5 mg polymer on an averageof 5 mg of mesh. The coated meshes were dried at room temperature for 24h and then dried in a vacuum oven for 3 days. In some instances, thepolymers were spray coated onto large meshes, cut to the desired sizeand implanted. After weighing, the coated meshes were sealed into PMMAchambers (size: d=1 cm and h=0.5 cm) with Nylaflo Nylon membranefilters.

The sealed chambers were implanted subcutaneously onto the back of therabbits placing five chambers with samples and one control chamber withplain mesh on each side of the back of each rabbit.

Chambers were surgically removed at the indicated time points and themeshes were analyzed for polymer mass loss and molecular weight changes.The polymer on the mesh is dissolved by soaking in DMF containing 0.1%TFA. The solution is filtered through 0.45μ Teflon® syringe mountablefilters and transferred to analysis vials for analysis bygel permeationchromatography (GPC) to assess the changes in molecular weight of thepolymer.

FIG. 1 illustrates the in vivo change in molecular weight of thepolymers in rabbits implanted with meshes coated with (♦) poly(DTM-15-DTglutarate), (⋄) poly(DTPB glutarate), (●) poly(DTMB succinate), (□)poly(DTMB glutarate), (▴) poly(DT(DATE)glutarate) and (∘)poly(DTMB-10-DT succinate). Other than the control, the polymers in thisstudy have no remaining molecular weight at times ranging from about 50to about 180 days.

To assess the mass loss profile, the coated meshes can be washed, driedand weighed (final weight) after removal from the chambers. The massloss is determined by subtracting the final weight from the originalweight of the coated mesh. FIG. 2 illustrates the mass loss during invivo implantation in rabbits implanted with meshes coated with (♦)poly(DTM-15-DT glutarate), (⋄) poly(DTPB glutarate), (●) poly(DTMBsuccinate), (□) poly(DTMB glutarate), (▴) poly(DT(DATE) glutarate) and(∘) poly(DTMB-10-DT succinate). The polymers in this study, other thanthe control, show considerable mass loss by about 75 days (or earlier)in many cases. The control does not lose all of its mass during the timecourse of the study whereas these polymers of the invention do so.

Example 8 Drug Release

A polypropylene mesh was sonicated with acetone followed by isopropanoland dried at 50° C. overnight. The poly(DTMB-glutarate) polymer andrifampin to give a 5% loading were dissolved in a suitable solvent(tetrahydrafuran or methylene chloride). This solution was then filteredthrough 1 micron filter and spray coated on the mesh using Sonotek spraycoater. The mesh was allowed to dry in the hood for 1 hour and thendried under vacuum at room temperature to remove all solvent.

For drug release, calculated amounts of the devices (based on HighPerformance Liquid Chromatography sensitivity) were placed in 20 mLscintillation vials. PBS (10 mL) was added, the vials capped and placedin an incubator-shaker at 37° C. At predetermined time intervals, thebuffer was pipetted out and analyzed by HPLC. The buffer was thenreplaced with 10 mL of fresh buffer. The kinetics of drug release wasobtained by plotting the cumulative drug released against time (FIG. 3).

A poly(DTMB-glutarate) film with a 5% loading of rifampin, a 5% loadingof minocycline, or both, is prepared as generally by the casting methoddescribed in U.S. Ser. No. 12/058,060, filed Mar. 28, 2008. Once dry,the films are cut into small pieces and placed into a vial containingPBS. Aliquots of buffer are removed periodically for analysis andreplaced with fresh buffer. Samples are analyzed by HPLC to determinethe cumulative amount of released rifampin or minocycline.

We claim:
 1. A polymer comprising one or more monomer units representedby either of the formulas:

wherein from zero to five R substituents are present at any position onthe phenyl ring, and each R is independently linear or branched,substituted or unsubstituted, saturated or unsaturated alkyl, aryl,alkylaryl, heteroatom-containing alkyl or aryl, alkylcycloalkyl, alkoxy,aryloxy or alkylether having from 1 to 20 carbon atoms; halide; nitro;—(R₂)_(r)O((CR₃R₄)_(a)O)_(s)—R_(s); —O((CR₃R₄)_(a)O)_(s)—R₅; —C(O)—R₅;—(R₂)_(b)O(O)—YR₆; a protected hydroxyl group; a protected amino groupor a protected carboxylic acid group; Y is —O— or —NH—; each R₂ islinear or branched, lower alkylene or lower alkenylene; each R₃ and R₄is independently hydrogen, or linear or branched lower alkyl; each R₅ isindependently linear or branched, substituted or unsubstituted,saturated or unsaturated alkyl; each R₆ is hydrogen; saturated orunsaturated alkyl, aryl or alkylaryl having from 1 to 20 carbon atoms;or —(R₂)_(r)O((CR₃R₄)_(a)O)_(s)—R₅; R₇ and R₈ are independently a bond,or linear or branched, substituted or unsubstituted alkyl, alkenyl oralkynyl having from 1 to 20 carbon atoms, each a is independently 1 to4; each b is independently zero or one; each r is independently 1 to 4;each s is independently 1 to
 5000. 2. The polymer of claim 1, where saidmonomer is represented by the formula:


3. The polymner of claim 2, wherein R₇ is —CH₂—CH₂— and R₈ is —CH₂—. 4.The polymer of claim 3, wherein said monomer is represented by theformula:


5. The polymer of claim 3, wherein said monomer is represented by theformula:


6. The polymer of claim 2, wherein R₇ is a bond and R₈ is —CH₂—.
 7. Thepolymer of claim 6, wherein said monomer is represented by the formula:


8. The polymer of claim 6, wherein said monomer is represented by theformula:


9. The polymer of claim 1, where said monomer is represented by theformula:


10. The polymer of claim 9, wherein R₇ is —CH₂—CH₂— and R₈ is —CH₂—. 11.The polymer of claim 10, wherein said monomer is represented by theformula:


12. The polymer of claim 9, wherein R₇ is a bond and R₈ is —CH₂—. 13.The polymer of claim 12, wherein said monomer is represented by theformula:


14. The polymer of claim 10, wherein said monomer is represented by theformula:


15. The polymer of claim 3, wherein said monomer is represented by theformula:


16. The polymer of claim 10, wherein said monomer is represented by theformula: